Lymphocytes exist in a resting state and require stimulation by antigen to proliferate and mount an effective immune response. In the case of T cells, this signal is delivered by major histocompatibility complex (MHC)-bound antigen signaling through T cell receptors (TCR). Full activation of T cells requires the input of various co-stimulatory and co-inhibitory pathways in addition to TCR activation (Croft, M. (2003) Nat. Rev. Immunol. 3:609).
Programmed Death 1, also known as PD-1 and CD279, is a 55 kDa cell surface, co-inhibitory receptor that is expressed mainly by lymphocytes, especially T cells (Blank, C. (2005) Cancer Immunol. Immunother. 54:307). The ligands for PD-1 include PD-L1, also known as B7-H1 and CD274, and PD-L2, also known as B7-DC and CD273. PD-1:PD-L1 or PD-1:PD-L2 interaction results in inhibition of T cell activation, leading to reduced proliferation, pro-inflammatory cytokine secretion, and T cell effector functions, such as T cell cytolysis (Freeman, G. (2000) J. Exp. Med. 192:1027; Latchman, Y. (2001) Nat. Immunol. 2:261; Rodig, N. (2003) Eur. J. Immunol. 33:3117).
In healthy individuals, PD-1 expression is induced by activation of T cells and declines after an immune response successfully eliminates a pathogen (Vibhakar, R. (1997) Exp. Cell Res. 232:25; Zajac, A. (1998) J. Exp. Med. 188:2205). Prolonged antigen stimulation in an unsuccessful immune response in some instances leads to elevated PD-1 expression and an “exhausted” T cell phenotype (Zajac, A. (1998) J. Exp. Med. 188:2205). Knockout of PD-1 in mice is not fatal and in a non-obese mouse diabetic model, knockout of the PD-1 ligand, PD-L1, results in accelerated development of immune mediated diseases (Wang, J. (2005) Proc. Natl. Acad. Sci USA 102:1823). Therefore, its primary role is believed to be in controlling immune responses to prevent the development of autoimmune disorders by down regulating T cell activity.
Many tumors have been shown to have increased expression levels of the ligands (PD-L1 and PD-L2) required for the negative regulation of lymphocytes by PD-1. This is especially true for PD-L1. Squamous cell carcinoma, colon adenocarcinoma, and breast adenocarcinoma have all been shown to have elevated levels of PD-L1 (Brown, J. (2003) J. Immunol. 170:1257). Furthermore, transgenic expression of PD-L1 on tumors in mice leads to increased tumorigenesis and invasion (Iwai, Y. (2002) Proc. Natl. Acad. Sci. USA 99:12293) and tumor growth in mouse melanoma models is abrogated by PD-1 knockout (Iwai, Y. (2005) Int. Immunol. 17:133).
These preclinical studies provide evidence that enhancing T cell function using anti-PD-1 antibodies is a promising treatment for immune dysfunctional disorders, for example cancer. Clinical studies also support this hypothesis. Blockade of immune checkpoint inhibitors, such as through the use of anti-PD-1 antibodies, has demonstrated clinical activity in several types of solid tumors (Brahmer, J. (2010) J. Clin. Oncol. 28:3167; Brahmer J. (2012) N. Engl. J. Med. 366:2455; Hamid, 0. (2013) N. Engl. J. Med. 369:134; Topalian, S. (2014) J. Clin. Oncol. 32:1020; Wolchok, J. (2013) N. Engl. J. Med. 369:122). The first immune checkpoint inhibitor, a fully human immunoglobulin (Ig) G1 monoclonal antibody that blocks cytotoxic T lymphocyte antigen 4 (CTLA4), was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in 2011. Three years later, the US FDA approved the first anti-PD-1 antibody for the treatment of advanced melanoma and the first published Phase III trial of PD-1 blockade in the US came in 2015 (Robert, C. (2015) N. Engl. J. Med. 372:320).
While PD-1 appears to be a promising target for the therapeutic treatment, there remains a need to develop improved compositions able to block the interaction of PD-1 with its ligand PD-L1 and PD-L2.